Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) induced in rodents by activated CD4+ T cells specific for various myelin proteins such as myelin basic protein and proteolipid protein. The disease is characterized by breach of the blood-brain barrier, perivascular infiltration of leukocytes into the CNS, local inflammation and demyelination in the form of plaques. In this study, we evaluated the effect of administration of antibodies to two members of the beta 2 integrin sub-family of adhesion molecules, CD11a and CD11b, on the onset and progression of EAE. CD11a and CD11b are involved in cell-cell interactions leading to T cell and macrophage extravasation to inflammatory sites and T cell activation. Our results show that anti-CD11a antibodies could completely block the induction of EAE and anti-CD11b antibodies significantly delayed the onset and diminished the severity of clinical signs of EAE even when injections were initiated at the first appearance of clinical signs.
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PMID:Both anti-CD11a (LFA-1) and anti-CD11b (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis. 749 3

Cells from 25 mice at different stages of experimental autoimmune encephalomyelitis (EAE) adoptively transferred using lymph node cells sensitized to a synthetic encephalitogenic peptide of myelin basic protein (p87-99) were examined for reactivity to a different encephalitogenic myelin antigen, proteolipid protein (PLP). Cellular reactivity to a synthetic encephalitogenic peptide of PLP (pPLP) was found in 3/5 mice with acute EAE, 4/9 with chronic EAE, 1/6 mice with EAE in remission, and 0/5 during relapse. No proliferation to pPLP was seen in naive mice or in healthy mice immunized with p87-99. Two of 13 mice developed typical EAE after the serial transfer of cells from animals with p87-99-induced EAE had been activated with pPLP in vitro. Controls consisted of recipients of (a) pPLP-activated cells from naive donors or donors immunized with a nonencephalitogenic MBP peptide, (b) cells from mice immunized with MBP activated in vitro with irrelevant antigen, or (c) ovalbumin-activated cells serially transferred from mice with adoptively transferred EAE. No control mice developed signs. These results suggest that during the course of myelin breakdown caused by an immune response to one myelin component (MBP), autoimmune reactivity to at least one additional myelin antigen (PLP) can arise. Furthermore, the acquired cellular reactivity to additional myelin components may be sufficient in some cases to induce disease itself, perhaps lending insight into mechanisms involved in disease progression.
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PMID:Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. 751 16

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.
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PMID:Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. 752 Jun 5

Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-beta after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.
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PMID:Antigen-driven tissue-specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse. 752 60

Previously, six T cell clones, which are specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) peptide residues 139 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use diverse TCR genes. To design TCR antagonist peptides that could interfere with the activation of these clones in vitro and inhibit experimental allergic encephalomyelitis (EAE) in vivo, we first determined the TCR and MHC contact residues of the encephalitogenic peptide. The analysis indicated that residues 144 (tryptophan) and 147 (histidine) were the TCR binding sites and that residues 145 (leucine) and 148 (proline) were important for MHC class II (IAs) binding. On the basis of this information, a peptide analogue (leucine 144/arginine 147), in which both of the major TCR contact residues were substituted, was synthesized. This analogue acts as a TCR antagonist for the panel of PLP 139-151-specific T cell clones, does not cause EAE by itself, blocks the induction of disease by the native 139-151 peptide, and prevents clinical disease progression if administered at the first signs of disease. Thus, although multiple TCR genes are used by PLP 139-151-specific clones, a single peptide analogue can interfere with the disease process. This approach should be feasible for designing peptide analogues that can be tested for therapeutic efficacy in human autoimmune diseases in which the pathogenic Ags are known and TCR use is diverse.
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PMID:A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. 752 58

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) and can be induced by inoculation of animals with homogenized CNS tissue or highly purified myelin proteins such as myelin basic protein (MBP) or proteolipid protein (PLP). It is widely studied as a possible animal model of multiple sclerosis. We performed the present neurophysiological study to define the location of nerve conduction abnormalities in EAE induced by immunization with PLP (PLP-EAE) and in EAE induced by immunization with MBP (MBP-EAE) in the Lewis rat. In rats with tail weakness due to acute PLP-EAE, conduction was normal in the spinal nerve roots and peripheral nerves but there was evidence of conduction block in a high proportion of the fibres in the dorsal columns of the lumbosacral spinal cord. In contrast, in acute MBP-EAE, there was conduction block in a high proportion of fibres in the sacral dorsal and ventral roots of the peripheral nervous system (PNS) and in the dorsal columns of the lumbosacral spinal cord. The distribution of nerve conduction abnormalities is consistent with previous histological studies showing that inflammation and primary demyelination are restricted to the CNS in PLP-EAE, but are present in the CNS and in the spinal roots of the PNS in MBP-EAE. The restriction of functional abnormalities to the CNS in PLP-EAE but not in MBP-EAE may have implications for the human inflammatory demyelinating diseases, including multiple sclerosis.
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PMID:Conduction abnormalities are restricted to the central nervous system in experimental autoimmune encephalomyelitis induced by inoculation with proteolipid protein but not with myelin basic protein. 752 6

The authors present a brief historical sketch of the development of our understanding of immune responses to myelin proteolipid protein (PLP) and the acceptance of PLP as a potent antigen in the induction of experimental allergic encephalomyelitis (EAE). The distinct characteristics of the PLP molecule that may contribute to complex immune responses to this protein are reviewed and these responses are compared with those to MBP, both in the pathology of EAE and at the level of the T cell. Recent evidence demonstrating differences between T cell responses to PLP and MBP is reviewed. Finally, the potential contribution of immune responses to PLP in human diseases, particularly multiple sclerosis (MS), that have been identified to date are then summarized.
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PMID:Minireview: autoimmune responses to myelin proteolipid protein. 752 54

This article reviews recent advances in understanding the role of myelin proteolipid protein (PLP) in autoimmune demyelination. It is drawn largely from work published within the last ten years and discusses the immunology of PLP in the historical context of what has been learned from extensive studies on the immune response to myelin basic protein (MBP). Despite the fact that PLP is the major protein constituent of mammalian myelin, its role in autoimmune demyelination has not been widely recognized. The lack of understanding about the immunology of PLP is a direct result of the biochemical characteristics of the protein. PLP is a highly hydrophobic membrane protein with limited aqueous solubility. The hydrophobicity of PLP has thwarted immunologic studies of the intact protein. Recent work has circumvented the technical obstacles of studying the intact protein by using soluble synthetic PLP peptides. This approach has rapidly resulted in a more definitive understanding of the immune response to PLP. Presently, the data indicate that: i) PLP is a major central nervous system (CNS) specific encephalitogen; ii) CD4+ T cell reactivity to discrete PLP peptide determinants can mediate the development of acute, chronic relapsing, and chronic progressive experimental autoimmune encephalomyelitis (EAE); and iii) T cell reactivity to multiple PLP determinants occurs in patients with multiple sclerosis (MS), the major human CNS demyelinating disease.
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PMID:Peptide determinants of myelin proteolipid protein (PLP) in autoimmune demyelinating disease: a review. 752 55

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that can be transferred to naive mice via CD4+ T cells isolated from appropriately immunized mice. We have evaluated the effects of recombinant murine interleukin 12 (rmIL-12), a potent inducer of interferon gamma (IFN-gamma) and promoter of Th1 T cell development, on the course of adoptively transferred EAE. The transfer of lymph node cells (LNC) isolated from proteolipid protein (PLP)-primed animals and stimulated in vitro with PLP to naive mice resulted in a progressive paralytic disease culminating in complete hind limb paralysis in the majority of the recipients. When mice were injected with LNC that had been stimulated in vitro with PLP in the presence of rmIL-12, the subsequent course of disease was more severe and prolonged. The addition of rmIL-12 during the in vitro stimulation with PLP resulted in a 10-fold increase in IFN-gamma and a 2-fold increase in tumor necrosis factor (TNF) alpha in the supernatants, relative to LNC stimulated with PLP alone. However, neutralization of IFN-gamma or TNF-alpha in vitro with specific antibodies did not abrogate the ability of rmIL-12 to exacerbate the subsequent disease. Similarly, mice treated with rmIL-12 in vivo after the transfer of antigen-stimulated LNC developed a more severe and prolonged course of disease compared with vehicle-treated control animals. In contrast, treatment of mice with an antibody to murine IL-12 after cell transfer completely prevented paralysis, with only 40% of the mice developing mild disease. These results demonstrate that in vitro stimulation of antigen primed LNC with PLP and rmIL-12 enhances their subsequent encephalitogenicity. Furthermore, inhibition of endogenous IL-12 in vivo after LNC transfer prevented paralysis, suggesting that endogenous IL-12 plays a pivotal role in the pathogenesis of this model of autoimmune disease.
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PMID:Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. 752 73

Immunization of animals with myelin proteolipid protein (PLP) causes experimental autoimmune encephalomyelitis (EAE), a disease model that shares many features with human multiple sclerosis (MS). The SJL/J (H-2s) mouse is widely used in EAE studies because of its high disease susceptibility. Previous studies have shown that sequences 139-151 HCLGKWLGHPDKF and 178-191 NTWTTCQSIAFPSK represent distinct co-immunodominant encephalitogenic determinants of PLP for SJL/J mice. In the present study, we identify a third distinct PLP encephalitogenic peptide for SJL/J mice. Following immunization with PLP 104-117 KTTICGKGLSATVT, 10/14 SJL/J mice developed clinical and histological EAE with a mean time of onset of 38 days (18-65 days). T cell lines generated from SJL/J mice immunized with p104-117 were predominantly (> 90%) CD3+, CD4+, alpha beta TCR+, CD8dim, gamma delta TCRdim T cells and responded in an Ag-specific, I-A(s)-restricted manner to p104-117. Upon adoptive transfer of 16-40 x 10(6) T line cells, EAE was produced in naive SJL/J recipients 20-34 days after transfer. The delayed onset of both active and passive disease may be related to the non-immunodominant, cryptic nature of p104-117 in SJL/J mice. Lymph node cells from SJL/J mice immunized with either whole PLP or with pooled encephalitogenic PLP peptides responded to challenge with the immunodominant PLP determinants p139-151 and p178-191 but did not respond to p104-117. The existence of three distinct PLP encephalitogenic T cell determinants for SJL/J mice suggests that susceptibility to EAE and perhaps MS may be related to promiscuous T cell recognition of multiple myelin protein determinants.
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PMID:Sequence 104-117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice. 753 82


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